Colorless, aqueous solutions of vitamin-k-active compounds and process for the manufacture of same



Patented July 31, 1945 COLOBLESS, AQUEOUS SOLUTIONS OF VITA-MlN-K-ACTIVE COMPOUNDS AND PROC- ESS FOR THE MANUFACTURE OF SAME KurtWarnat, Basel, Switzerland, ass i'gnor to Hoflmann-La Roche Inc.,Nntiey, N. 1., a corporation of New Jersey No Drawing. ApplicationSeptember 16, 1948, Se-

rial No. 502,704. 1942 3 Claims.

It has been found that colorless, aqueous solutions of vitamin-K-activecompounds, for instance tor ampuls, can be manuiactured ill thefollowing manner: The crude2-methyl-L4-dihydroxy-naphthalene-diphosphoric-acid tetra chloride,obtained by condensation of z-methyl- 1,4-dihydroxy-naphthalene withphosphorous oxy-chlorlde, is hydrolised with water in the presence of abase; the inorganic phosphates are precipitated by the addition of acalcium compound; the solution freed from phosphates is heated toboiling, and the precipitated Z-methyll,4-dihydroxy naphthalenediphosphoric-aclddicalcium salt, if desired, is transformed into othersalts by known methods. The aqueous solutions obtained may be filledinto ampuls dlrectly or, if desired, the salts can be precipitated fromthe solution and then re-dissolved in water.

The salts obtained according to the present process are, without furtherpurification, sumciently pure for direct use in therapy.

Example 1 A solution cl 1!) parts by weight of z-methyl-Ld-dihydroxy-naphthalene in 7100 parts by weight of pyridine is added to150 parts by weight of phosphorus cry-chloride while cooling thoroughly.After completion of the reaction, the diphosphoric-acid-dichloride isseparated from the precipitated pyridine hydrochloride by extractionwith benzene. The benzene solution is concentrated in vacuo and theresidue, without further purification, is hydrolised carefully withwater containing sodium hydroxide. The. neutral solution is mixed with asolution of parts by weight of calcium chloride, the total volumeamounting to about 300 to 500 parts by volume.

' The calcium phosphate deposited is filtered oh CnHsOsPaCaaAHcO part ofthe water of crystallisation escapes easily even at room temperature. Itdissolves more easily in cold than in warm water and can be useddirectly for the preparation oi. solutions for ampuls.

Example 2 To a well stirred mixture of 170 parts by weight oiphosphorus'oxy-chloride and 40 parts by weight oi toluene a suspensionoi! 17.4 parts by weight In Switzerland March 3,

of Z-methyl-1,4-dihydroxy-naphthalene in 50 parts by weight ofdimethyl-aniline and 150 parts by weight of toluene is added whilecooling. Alter completion of the reaction the excess phosphoricoxy-chloride and toluene are distilled oil in vacuo. The residue ishydrolised by the addition of water at a temperature of about 20-30" C.The aqueous solution is neutrallsed by the addition of sodium carbonateand inorganic phosphates are precipitated by the addition of parts byweight of calcium chloride. The phosphate-precipitate is filtered offand the filtrate amounting to a volume of about 500 to 1000 parts byvolume is heated to boiling. The calcium salt is obtained in a yield ofat least 80% of the theoretical.

Escmple'l llsl parts by weight oi 2-methyl-i,%-dihydrorry-naphthaleneare condensed as described in Example 2. After driving oh the excessphosphorous oxy-chloride and the toluene, the crudedlphosphoric-acid-dichloride is hydrolised with water while addingcalcium hydromde. Inorganic phosphates and the dimethyl-anilineprecipitated are separated ed, and the aqueous sclution is heated toboiling.

Example 4 20 parts by weight at the calcium salt of 2 methyl 1,4dihydrow naphthalene diphosphone-acid, manufactured according to maamples 1-3, are dmlved in 5% parts by weight of water at about iil C.Oxallc acid and sodium hydroxide are added until a pH of about 6-7 isreached and until a sample oi the filmte is free from calciumandoxalic-acid. Then the calcium oxalate is filtered ed. The solution ofthe sodium salt obtained can directh be used for injection purposes.

The sodium salt can be obtained in crystalline form by carefullyconceals-sting the filtrate in vacuo to a small volume, bringing the pHto about 8, and adding alcohol until an oil sepcrates. Upon rubbing witha glass-rod, and, it necessary, addition or seed crystals, the oil sooncrystallises. The crystallisation is completed by the addition of morealcohol. If necessary, the salt can be purified by dissolving in waterand recrystallising by the addition of alcohol. when the salt is driedexposed to air it contains 12 molecules of crystallisation water. Thesalt is not hygroscopic. For iniection purposes the aqueous solutionthereof can be filled into smpuls. the operation bolus carried out in anatmosphere of an inert as if desired.

I claim:

1.1:: the process for the manufacture of water-soluble salts of2-methyl-L4-dihydroaynaphthalene diphosphoric acid the steps whichcomprise hydrolysis: crude2-methyl-L4-dihydroxy-naphthalene-diphosphoric acid tetrachloride withwater in the presence of a base. removin: from the solution thusobtained any free phosphoric acid present therein by adding a calciumcompound forming calcium phosphate with water-soluble salts of2'-methyl-1,4-dihydroxynaphthalene diphosphoric acid the steps whichcomprise hydrolyzinz crude Q-methyl-iA-dihydroxy-naphthalenediphosphoric acidtetrachloridswithwatsrinthepnssuceoicalciumhydrozidassparatinaawcalciumphosphatsprecipitatedinthsresuitinasoiutionsndbcilin:thesolutioninthsprssencsofacalciumcompoundprecipitatinsthecalciumsaltofzmethyl-IA-dihydrcay-naphthalene,diphosphoric Home.

acid from the boilin 3.'In the process for the manufacture ofwater-soluble salts oi 2-methyl-i,4-dihydroxynaphthalene diphosphoricacid the steps which comprise hydrolysinz crude 2-methyi-1,4-dihydroxynaphthalene diphosphoric acid tetrachloride with water containing sodiumhydroxide, mixing the neutral solution with an aqueous solution ofcalcium hydroxide in an amount whereby any free phosphoric acid presentin the solution is precipitated as calcium phosphate, and the calciumsalt of 2-methyl-L4-dihydroxy-naphthalene diphosphoric acid isprecipitated from the solution freed from calcium phosphate uponboiling.

KURT ,WARNAT.

